Rosell R, Monzó M, Pifarré A, Ariza A, Sánchez J J, Moreno I, Maurel J, López M P, Abad A, de Anta J M
Medical Oncology Service, Laboratory of Molecular Biology of Cancer, Department of Pathology, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain.
Clin Cancer Res. 1996 Jun;2(6):1083-6.
We have previously demonstrated a strong association between K-ras gene mutations, as determined by PCR followed by allele-specific oligonucleotide hybridization (ASO-h), and survival in non-small cell lung cancer patients. The purpose of this study was to determine the relationship between tumor aggressiveness and specific-type K-ras point mutations in non-small cell lung cancer. We developed procedures to examine the status of the K-ras gene by ASO-h and by single-strand conformation polymorphism assay of DNA obtained from formalin-fixed paraffin-embedded tumors. K-ras point mutations at codons 12 and 61 were assessed in 275 consecutively treated stage I-IV non-small cell lung cancers. Among patients with stage I disease, median survival time was 41.5 months in those whose tumors had no evidence of K-ras mutations and 27 months in those with K-ras 12 mutations; among patients with stage IIIA disease, median survival time was 7 months in those with K-ras codon 12 aspartic and serine mutations and 15 months for those with other K-ras mutations (P = 0.01). In a multivariate analysis, specific-type K-ras codon 12 point mutation remained a strong predictive factor (hazard ratio for death, 2.06; 95% confidence interval, 1.11-3.81; P = 0.02) after adjustment for other evaluated factors, including TNM stage and histology. Thus, we concluded that in patients with non-small cell lung cancer, specific K-ras 12 point mutations detected by DNA amplification and either ASO-h or single-strand conformation polymorphism methods predicted a significantly increased risk of recurrence and death, independently of stage and histology.
我们之前已经证明，通过聚合酶链反应（PCR）继以等位基因特异性寡核苷酸杂交（ASO-h）检测到的K-ras基因突变与非小细胞肺癌患者的生存率之间存在密切关联。本研究的目的是确定非小细胞肺癌中肿瘤侵袭性与特定类型的K-ras点突变之间的关系。我们开发了相关程序，通过ASO-h以及对从福尔马林固定石蜡包埋肿瘤中获取的DNA进行单链构象多态性分析来检测K-ras基因的状态。对275例连续接受治疗的Ⅰ-Ⅳ期非小细胞肺癌患者评估了第12和61密码子处的K-ras点突变情况。在Ⅰ期疾病患者中，肿瘤无K-ras突变证据者的中位生存时间为41.5个月，而有K-ras 12突变者为27个月；在ⅢA期疾病患者中，K-ras第12密码子发生天冬氨酸和丝氨酸突变者的中位生存时间为7个月，其他K-ras突变者为15个月（P = 0.01）。在多变量分析中，在对包括TNM分期和组织学等其他评估因素进行校正后，特定类型的K-ras第12密码子点突变仍然是一个强有力的预测因素（死亡风险比为2.06；95%置信区间为1.11 - 3.81；P = 0.02）。因此，我们得出结论，在非小细胞肺癌患者中，通过DNA扩增以及ASO-h或单链构象多态性方法检测到的特定K-ras 12点突变预测复发和死亡风险显著增加，且独立于分期和组织学。
